Escalating dose-multiple binge methamphetamine treatment elicits neurotoxicity, altering gut microbiota and fecal metabolites in mice
Escalating dose-multiple binge methamphetamine treatment elicits neurotoxicity, altering gut microbiota and fecal metabolites in mice
复制标题
递增剂量多次暴食甲基苯丙胺治疗会引起神经毒性，改变小鼠的肠道微生物群和粪便代谢物
DOI：
10.1016/j.fct.2020.111946
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发表时间：
2021-02-01
影响因子：
4.3
通讯作者：
Wang, Qi
中科院分区：
文献类型：
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作者：
Chen, Li-Jian;Zhi, Xu;Wang, Qi
甲基苯丙胺是一种令人上瘾的非法精神刺激药物，可导致多器官功能障碍，特别是在中枢神经系统(CNS)。肠道微生物区系通过肠道-脑轴(GBA)参与了多种中枢神经系统相关疾病的发展。然而，冰毒对肠道微生物区系和粪便代谢产物的影响尚不清楚，与冰毒所致神经毒性的关系也尚不清楚。在本研究中，我们通过将BALB/c小鼠暴露于递增剂量的多次暴食方案中，研究了冰毒对纹状体神经毒性和结肠损伤的影响，然后用Western印迹分析了蛋白质的表达。我们进一步对粪便样本中的16个S rRNA基因进行了检测和测序，并进行了基于超高效液-质联用的代谢组学分析肠道微生物和粪便代谢物。冰毒可显著下调酪氨酸羟化酶(TH)蛋白表达，上调MAOA、Beclin1、ATG5和LC3-II蛋白表达。方法通过激活Toll样受体4(TLR4)/髓系分化因子88(MyD88)/核因子-kappa B(NF-kappa B)途径上调炎症相关因子caspase1、TNF-α和IL-18的表达，减少occludin蛋白的表达。此外，冰毒暴露改变了肠道微生物区系的α和β多样性。具体地说，接触冰毒增加了致病菌的相对丰度，但减少了益生菌的相对丰度。代谢组学结合浓缩分析表明，接触冰毒会改变粪便代谢物。我们的发现表明，冰毒暴露诱导了中枢神经系统的自噬，增加了肠道自噬菌群，导致粪便代谢物在自噬途径中积累，并导致肠炎。此外，冰毒通过增加肠道内致病菌的相对丰度，减少肠道TJ蛋白的表达，从而促进肠道炎症。
Methamphetamine (METH) is an addictive and illegal psychostimulant drug that can cause multiple organ dysfunction, especially in the central nervous system (CNS). Gut microbiota have been implicated in development of various CNS-related diseases, via the gut-brain axis (GBA). However, effect of METH in the alteration of gut microbiota and fecal metabolites is unclear, whereas the relationship with METH-induced neurotoxicity remains unknown. In the current study, we investigated effect of METH on neurotoxicity in striatum and colonic damage by exposing BALB/c mice to an escalating dose-multiple binge regimen, and then analyzed protein expression using Western blot analysis. We further detected and sequenced the 16 S rRNA gene in fecal samples, and performed ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to analyze gut microbes and fecal metabolites. Exposure to METH significantly downregulated tyrosine hydroxylase (TH) proteins, but upregulated MAOA, Beclin1, Atg5, and LC3-II. METH up-regulated inflammation-related factors, such as caspase1, TNF-alpha and IL-18, by activating the toll-like receptors 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor kappa B (NF-kappa B) pathway and reduced occludin protein expression. In addition, METH exposure changed alpha and beta diversities of gut microbiota. Specifically, METH exposure elevated relative abundances of pathogenic bacteria, but reduced those of probiotics. Metabolomics, combined with enrichment analyses revealed that METH exposure altered fecal metabolites. Our findings suggest that METH exposure induced autophagy in the CNS, elevated intestinal autophagy flora, leading to accumulation of fecal metabolites in the autophagy pathway, and causing enteritis. Moreover, METH promoted intestinal inflammation by increasing the relative abundance of the pathogenic bacteria in the intestinal tract, and reduced intestinal TJ protein expression.